Increased release of excitatory amino acids in rat locus coeruleus in κ-opioid agonist dependent rats precipitated by nor-binaltorphimine

Extracellular fluid levels of glutamate and aspartate in the locus coeruleus (LC) during nor-binaltorphimine (nor-BNI)-precipitated withdrawal from butorphanol, (5α,7α,8β)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro dec-8-yl]-benzeneacetamide (U-69,593), or morphine were measured in rats. When the microdialysis probe was located in the core of the LC, increases in glutamate and aspartate were noted after nor-BNI (48 nmol/50 μl, LC)-precipitated withdrawal in rats that had been intracerebroventricularly infused with butorphanol (26 nmol/1 μl/h) or U-69,593 (26 nmol/10 μl/h) for 3 days. The glutamate and aspartate levels in the LC markedly increased in the butorphanol- or U-69,593-dependent rats within 60 min following administration of nor-BNI. However, there was no significant increase in levels of glutamate, and only a slight increase in levels of aspartate, after nor-BNI treatment of the morphine (26 nmol/1 μl/h)-infused rats. Behavioral signs of withdrawal (teeth-chattering, wet-dog shakes, etc.) were observed following nor-BNI challenge in the butorphanol- or U-69,593-infused rats, with only minimal signs in the morphine-infused rats, and none in the saline-infused controls. These results directly suggest that κ-opioid receptors and excitatory amino acids within the LC mediate withdrawal in animals dependent on butorphanol or U-69,593, but not on morphine.